Over the last three decades, controlled drug release technology has attracted researchers because it is an efficient means of administering bioactive agents to patients. With genetic engineering products becoming increasingly available, controlled drug release systems have attained a new level of interest due to their excellent performance and high economic potential. Of the various modalities undergoing intense study, the erodible polymeric systems stand out because they do not have to be removed once implanted and many biocompatible polymers are known. Among these, polyanhydrides have been tested extensively in controlled drug release applications to the point where polymer-drug matrices are now available for treating human brain tumors. However, the vast majority of polyanhydrides are linear, their backbone cleavage generally leads to the formation of "internal" erosion fronts resulting in variable drug release rates, and their use in humans is limited to short-term (one to two months) applications. The ultimate goal of this project is to develop a monolith-type, polymer-drug matrix based on branched or cross-linked, amino acid-containing polyanhydrides capable of releasing peptides and proteins at predictable rates for months to years after implantation in animals and humans. The underlying hypothesis is that these new polyanhydrides can be made to degrade at the surface by altering their chemical structure or the matrix formulation procedure. The specific aims are: 1) to synthesize and characterize branched or cross-linked poly(anhydride-co-imides) based on an amino acid-containing prepolymer and a prepolymer of a spacer molecule such as sebacic acid or glycolic acid; 2) to formulate polymer-drug matrices based on the polymers synthesized and either cyclosporin A or porcine insulin as test peptides/proteins; 3) to incubate these matrices in aqueous media and determine the polymer degradation/drug release rates; 4) to determine the immunoreactivity of the test proteins throughout the matrix formulation and incubation procedures; and 5) to implant the polymer-cyclosporin A matrices in normal rats for periods of up to two months to determine the polymer degradation and drug release rates. The methods proposed include polymer synthesis and characterization using various chromatographic and spectrophotometric techniques; formulation of polymer-drug matrices and incubation in vitro, accounting for all the species of interest; activity testing of the entrapped peptides and proteins by radioimmunoassay; and in vivo implantation and follow up of the polymer-cyclosporin A matrices in rats. This integrated approach involving fundamental polymer chemistry, as well as in vitro and in vivo testing, will lead to a more rational design of these polyanhydride-drug matrices.